er than the combination. acute otitis media for the treatment of acute otitis media in pediatric patients due to susceptible strains of streptococcus pneumoniae or haemophilus influenzae when in the judgment of the physician sulfamethoxazole and trimethoprim offers some advantage over the use of other antimicrobial agents. to date, there are limited data on the safety of repeated use of sulfamethoxazole and trimethoprim tablets in pediatric patients under two years of age. sulfamethoxazole and trimethoprim tablets are not indicated for prophylactic or prolonged administration in otitis media at any age. acute exacerbations of chronic bronchitis in adults for the treatment of acute exacerbations of chronic bronchitis due to susceptible strains of streptococcus pneumoniae or haemophilus influenzae when a physician deems that sulfamethoxazole and trimethoprim could offer some advantage over the use of a single antimicrobial agent. shigellosis for the treatment of enteritis caused by susceptible strains of shigella flexneri and shigella sonnei when antibacterial therapy is indicated. pneumocystis jirovecii pneumonia for the treatment of documented pneumocystis jirovecii pneumonia and for prophylaxis against p. jirovecii pneumonia in individuals who are immunosuppressed and considered to be at an increased risk of developing p. jirovecii pneumonia. traveler’s diarrhea in adults for the treatment of traveler’s diarrhea due to susceptible strains of enterotoxigenic e. coli .

layed lung injury; anaphylaxis and circulatory shock have occurred with the administration of sulfamethoxazole and trimethoprim products, including sulfamethoxazole and trimethoprim (see adverse reactions ). cough, shortness of breath and pulmonary infiltrates potentially representing hypersensitivity reactions of the respiratory tract have been reported in association with sulfamethoxazole and trimethoprim treatment. other severe pulmonary adverse reactions occurring within days to week of sulfamethoxazole and trimethoprim initiation and resulting in prolonged respiratory failure requiring mechanical ventilation or extracorporeal membrane oxygenation (ecmo), lung transplantation or death have also been reported in patients and otherwise healthy individuals treated with sulfamethoxazole and trimethoprim products. circulatory shock with fever, severe hypotension, and confusion requiring intravenous fluid resuscitation and vasopressors has occurred within minutes to hours of re-challenge with sulfamethoxazole and trimethoprim products, including sulfamethoxazole and trimethoprim, in patients with history of recent (days to weeks) exposure to sulfamethoxazole and trimethoprim. sulfamethoxazole and trimethoprim should be discontinued at the first appearance of skin rash or any sign of a serious adverse reaction. a skin rash may be followed by a more severe reaction, such as stevens-johnson syndrome, toxic epidermal necrolysis, dress, afnd, agep, hepatic necrosis, or serious blood disorders (see precautions and adverse reactions ). clinical signs, such as rash, pharyngitis, fever, arthralgia, cough, chest pain, dyspnea, pallor, purpura or jaundice may be early indications of serious reactions. thrombocytopenia sulfamethoxazole and trimethoprim-induced thrombocytopenia may be an immune-mediated disorder. severe cases of thrombocytopenia that are fatal or life threatening have been reported. thrombocytopenia usually resolves within a week upon discontinuation of sulfamethoxazole and trimethoprim. streptococcal infections and rheumatic fever the sulfonamides should not be used for treatment of group a β-hemolytic streptococcal infections. in an established infection, they will not eradicate the streptococcus and, therefore, will not prevent sequelae such as rheumatic fever. clostridioides difficile associated diarrhea clostridioides difficile associated diarrhea (cdad) has been reported with use of nearly all antibacterial agents, including sulfamethoxazole and trimethoprim, and may range in severity from mild diarrhea to fatal colitis. treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of c. difficile . c. difficile produces toxins a and b which contribute to the development of cdad. hypertoxin producing strains of c. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. cdad must be considered in all patients who present with diarrhea following antibiotic use. careful medical history is necessary since cdad has been reported to occur over two months after the administration of antibacterial agents. if cdad is suspected or confirmed, ongoing antibiotic use not directed against c. difficile may need to be discontinued. appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of c. difficile , and surgical evaluation should be instituted as clinically indicated. risk associated with concurrent use of leucovorin for pneumocystis jirovecii pneumonia treatment failure and excess mortality were observed when sulfamethoxazole and trimethoprim was used concomitantly with leucovorin for the treatment of hiv positive patients with p. jirovecii pneumonia in a randomized placebo-controlled trial 4 . avoid co-administration of sulfamethoxazole and trimethoprim and leucovorin during treatment of p . jirovecii pneumonia.

66 30 1½ 88 40 2 or 1 ds tablet for patients with impaired renal function when renal function is impaired, a reduced dosage should be employed using the following table: creatinine clearance (ml/min) recommended dosage regimen above 30 usual standard regimen 15 to 30 ½ the usual regimen below 15 use not recommended acute exacerbations of chronic bronchitis in adults the usual adult dosage in the treatment of acute exacerbations of chronic bronchitis is 1 sulfamethoxazole and trimethoprim double strength tablet or 2 sulfamethoxazole and trimethoprim single strength tablets every 12 hours for 14 days. pneumocystis jirovecii pneumonia treatment adults and children the recommended dosage for treatment of patients with documented pneumocystis jirovecii pneumonia is 75 mg/kg to 100 mg/kg sulfamethoxazole and 15 mg/kg to 20 mg/kg trimethoprim per 24 hours given in equally divided doses every 6 hours for 14 to 21 days 12 . the following table is a guideline for the upper limit of this dosage: weight dose – every 6 hours lb kg tablets 18 8 - 35 16 1 53 24 1½ 70 32 2 or 1 ds tablet 88 40 2½ 106 48 3 or 1½ ds tablets 141 64 4 or 2 ds tablets 176 80 5 or 2½ ds tablets for the lower limit dose (75 mg/kg sulfamethoxazole and 15 mg/kg trimethoprim per 24 hours) administer 75% of the dose in the above table. prophylaxis adults: the recommended dosage for prophylaxis in adults is 1 sulfamethoxazole and trimethoprim double strength tablet daily 13 . children: for children, the recommended dose is 750 mg/m 2 /day sulfamethoxazole with 150 mg/m 2 /day trimethoprim given orally in equally divided doses twice a day, on 3 consecutive days per week. the total daily dose should not exceed 1,600 mg sulfamethoxazole and 320 mg trimethoprim 14 . the following table is a guideline for the attainment of this dosage in children: body surface area dose – every 12 hours (m 2 ) tablets 0.26 - 0.53 ½ 1.06 1 traveler’s diarrhea in adults for the treatment of traveler’s diarrhea, the usual adult dosage is 1 sulfamethoxazole and trimethoprim double strength tablet or 2 sulfamethoxazole and trimethoprim single strength tablets every 12 hours for 5 days.

and circulatory shock have occurred with the administration of sulfamethoxazole and trimethoprim products, including sulfamethoxazole and trimethoprim (see warnings). hematologic: agranulocytosis, aplastic anemia, thrombocytopenia, leukopenia, neutropenia, hemolytic anemia, megaloblastic anemia, hypoprothrombinemia, methemoglobinemia, eosinophilia, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura. allergic reactions: stevens-johnson syndrome, toxic epidermal necrolysis, anaphylaxis, allergic myocarditis, erythema multiforme, exfoliative dermatitis, angioedema, drug fever, chills, henoch-schoenlein purpura, serum sickness-like syndrome, generalized allergic reactions, generalized skin eruptions, photosensitivity, conjunctival and scleral injection, pruritus, urticaria, rash, periarteritis nodosa, systemic lupus erythematosus, drug reaction with eosinophilia and systemic symptoms (dress), acute generalized erythematous pustulosis (agep), and acute febrile neutrophilic dermatosis (afnd) (see warnings ). gastrointestinal: hepatitis (including cholestatic jaundice and hepatic necrosis), elevation of serum transaminase and bilirubin, pseudomembranous enterocolitis, pancreatitis, stomatitis, glossitis, nausea, emesis, abdominal pain, diarrhea, anorexia. genitourinary: renal failure, interstitial nephritis, bun and serum creatinine elevation, renal insufficiency, oliguria and anuria, crystalluria and nephrotoxicity in association with cyclosporine. metabolic and nutritional: hyperkalemia, hyponatremia (see precautions: electrolyte abnormalities ), metabolic acidosis. neurologic: aseptic meningitis, convulsions, peripheral neuritis, ataxia, vertigo, tinnitus, headache. psychiatric: hallucinations, depression, apathy, nervousness. endocrine: the sulfonamides bear certain chemical similarities to some goitrogens, diuretics (acetazolamide and the thiazides) and oral hypoglycemic agents. cross-sensitivity may exist with these agents. diuresis and hypoglycemia have occurred. musculoskeletal: arthralgia, myalgia, rhabdomyolysis. respiratory: cough, shortness of breath and pulmonary infiltrates, acute eosinophilic pneumonia, acute and delayed lung injury, interstitial lung disease, acute respiratory failure (see warnings ). cardiovascular system: qt prolongation resulting in ventricular tachycardia and torsades de pointes , circulatory shock (see warnings ) . miscellaneous: weakness, fatigue, insomnia. to report suspected adverse reactions, contact amneal pharmaceuticals at 1-877-835-5472 or fda at 1-800-fda-1088 or www.fda.gov/medwatch .

ot a substrate of p-glycoprotein. approximately 70% of sulfamethoxazole and 44% of trimethoprim are bound to plasma proteins. the presence of 10 mg percent sulfamethoxazole in plasma decreases the protein binding of trimethoprim by an insignificant degree; trimethoprim does not influence the protein binding of sulfamethoxazole. peak blood levels for the individual components occur 1 to 4 hours after oral administration. the mean serum half-lives of sulfamethoxazole and trimethoprim are 10 and 8 to 10 hours, respectively. however, patients with severely impaired renal function exhibit an increase in the half-lives of both components, requiring dosage regimen adjustment (see dosage and administration section). detectable amounts of sulfamethoxazole and trimethoprim are present in the blood 24 hours after drug administration. during administration of 800 mg sulfamethoxazole and 160 mg trimethoprim b.i.d., the mean steady-state plasma concentration of trimethoprim was 1.72 mcg/ml. the steady-state mean plasma levels of free and total sulfamethoxazole were 57.4 mcg/ml and 68 mcg/ml, respectively. these steady-state levels were achieved after three days of drug administration 1 . excretion of sulfamethoxazole and trimethoprim is primarily by the kidneys through both glomerular filtration and tubular secretion. urine concentrations of both sulfamethoxazole and trimethoprim are considerably higher than are the concentrations in the blood. the average percentage of the dose recovered in urine from 0 to 72 hours after a single oral dose of sulfamethoxazole and trimethoprim is 84.5% for total sulfonamide and 66.8% for free trimethoprim. thirty percent of the total sulfonamide is excreted as free sulfamethoxazole, with the remaining as n 4 -acetylated metabolite 2 . when administered together as sulfamethoxazole and trimethoprim, neither sulfamethoxazole nor trimethoprim affects the urinary excretion pattern of the other. both sulfamethoxazole and trimethoprim distribute to sputum, vaginal fluid and middle ear fluid; trimethoprim also distributes to bronchial secretion, and both pass the placental barrier and are excreted in human milk. pharmacokinetics in pediatric patients a simulation conducted with data from a pharmacokinetic study in 153 infants and children demonstrated that mean steady-state auc and maximum plasma concentration of trimethoprim and sulfamethoxazole would be comparable between pediatric patients 2 months to 18 years receiving 8/40 (trimethoprim/ sulfamethoxazole) mg/kg/day divided every 12 hours and adult patients receiving 320/1,600 (trimethoprim/ sulfamethoxazole) mg/day. pharmacokinetics in geriatric patients the pharmacokinetics of sulfamethoxazole 800 mg and trimethoprim 160 mg were studied in 6 geriatric subjects (mean age: 78.6 years) and 6 young healthy subjects (mean age: 29.3 years) using a non-us approved formulation. pharmacokinetic values for sulfamethoxazole in geriatric subjects were similar to those observed in young adult subjects. the mean renal clearance of trimethoprim was significantly lower in geriatric subjects compared with young adult subjects (19 ml/h/kg vs. 55 ml/h/kg). however, after normalizing by body weight, the apparent total body clearance of trimethoprim was on average 19% lower in geriatric subjects compared with young adult subjects 3 . microbiology mechanism of action sulfamethoxazole inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid (paba). trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting the required enzyme, dihydrofolate reductase. thus, sulfamethoxazole and trimethoprim blocks two consecutive steps in the biosynthesis of nucleic acids and proteins essential to many bacteria. resistance in vitro studies have shown that bacterial resistance develops more slowly with both sulfamethoxazole and trimethoprim in combination than with either sulfamethoxazole or trimethoprim alone. antimicrobial activity sulfamethoxazole and trimethoprim has been shown to be active against most isolates of the following microorganisms, both i n vitro and in clinical infections as described in the indications and usage section. aerobic gram-positive bacteria streptococcus pneumoniae aerobic gram-negative bacteria escherichia coli (including susceptible enterotoxigenic strains implicated in traveler’s diarrhea) klebsiella species enterobacter species haemophilus influenzae morganella morganii proteus mirabilis proteus vulgaris shigella flexneri shigella sonnei other microorganisms pneumocystis jirovecii susceptibility testing for specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by fda for this drug, please see: https://www.fda.gov/stic.